Pathological response to neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC): A systematic review and meta-analysis.
Authors: Sebawe Syaj, Marah Akhdar, Obada Ehab Ababneh, Shadi Hamouri
Journal: Journal of Clinical Oncology (2022)

e20582 Background: The advantage of combining chemotherapy and immune checkpoint inhibitors (ICIs) in resectable non-small cell lung cancer (NSCLC) patients has recently been studied in clinical trial settings. We aim to systematically revise the evidence of efficacy and safety of neoadjuvant chemoimmunotherapy treatment. Methods: We carried out a systematic search on MEDLINE, Scopus, Cochrane, and ASCO meetings library. Screening was done to include clinical trials of stage I-IIIA NSCLC patients who underwent any combination of ICIs and chemotherapy. The primary outcomes were major pathological response (MPR) and pathological complete response (pCR), and the secondary outcomes were 24-month overall survival (OS) and safety measured by adverse events (AEs). A meta-analysis was conducted for intention-to-treat MPR and pCR outcomes, in addition to a mixed-effects meta-regression model to investigate the effect of PD-L1 expression, tumor mutational burden (TMB), N stage (AJCC 8 th ), tumor size and tumor histology on MPR and pCR. PD-L1+ patients were defined to have a tumor proportion score of more or equal to 1%. Results: We included 9 phase II clinical trials and 1 phase III trial, all consisting of 471 patients. Trials administered neoadjuvant chemotherapy agents like carboplatin (N = 6 studies), cisplatin (N = 5), nab-paclitaxel (N = 4), pemetrexed (N = 2), and others, either as a doublet- or a triplet-agent regimen. ICIs used were anti-PD-1 (N = 5), anti-PD-L1 (N = 3), or anti-CTLA-4 agents (N = 2). Meta-analysis of 447 patients from 9 trials showed a pooled MPR of 49.2% (95% CI: 34.8 to 63.7%) with high heterogeneity (I 2 = 87%, p &lt; 0.01). Pooling the pCR from 10 trials including 471 patients results in an estimate of 27.5% (95% CI: 17.2 to 38.2%) with significant heterogeneity (I 2 = 80%, p &lt; 0.01). Meta-regression has found a significant association between being PD-L1+ and achieving MPR (odds ratio = 3.82, 95% CI: 1.55 to 9.58). However, this effect diminished in the multiple meta-regression that included age, tumor histology, in addition to PD-L1 status. None of these factors was correlated to achieving a pCR. Investigating the effect of tumor size, T stage, N stage, or TMB on MPR or pCR was not possible due to underreported data. Three trials of 137 patients reported a 24-month OS of 84.4% (95% CI: 77.6 to 90.2%) with low heterogeneity (I 2 = 11%, p = 0.33). The most prevalent grade 3/4 AEs from the neoadjuvant treatment were neutropenia in 7.2% of patients, diarrhea in 3.2%, fatigue in 3.0%, and anemia in 2.1% of patients. The commonest any-grade AEs were fatigue (43.9%), alopecia (38.4%), diarrhea (31.6%), anemia (23.8%) and neutropenia (17.0%). Conclusions: The addition of ICIs to chemotherapy in neoadjuvant settings is an effective and feasible option. Effect of tumor size, PD-L1 status and TMB on MPR and pCR should be further investigated for better selection of treatment candidates.